The survival of patients with locally advanced cervix cancer and intermediate risk prostate cancer is compromised by suboptimal local/regional control. We hypothesize that by integrating brachytherapy primary tumor treatment with highly conformal IMRT that accurately delivers dose-per-fraction escalation to regions of known primary and metastatic nodal disease not adequately treated by brachytherapy will allow overall treatment time to be reduced and biologically effective dose to be increased beyond levels considered safe with current technology. To achieve these goals we will collaborate with Projects 1 and 2 to apply and clinically validate deformable image registration tools for accurately transferring information from biological imaging studies to planning x-ray computed tomography (CT) images (voxel labeling), mapping brachytherapy dose distributions onto IMRT planning images, and constructing 4-dimensional models (4D voxel trajectories) of patient anatomy based upon serial CT imaging. We will investigate a family of image-guided adaptive radiation therapy (IGART) based upon 4D voxel trajectories, probabilistic treatment planning, and off- and on-line plan adaptations to compensate for changes in patient anatomy. The aim of IGART is to minimize geometric delivery uncertainties arising from setup error and internal tissue motion so that dose-per-fraction escalation can be administered to the target tissue with minimum margins and maximum normal tissue avoidance. In Specific Aim 1. we will perform clinical studies in the two patient populations and implement and validate tools for quantifying 3D tissue deformation uncertainties and investigate methods for minimizing systematic errors arising from voxel labeling and brachytherapy dose mapping. Specific Aim 2 will develop approaches for constructing 4D voxel trajectories from serial CT images and assess their uncertainties. Optimal methods for estimating the patient's 4D anatomy configuration prior to each day's treatment will be investigated. Specific Aim 3 will perform simulated virtual clinical trials to identify and optimize the most appropriate form of IGART for maximizing clinical benefit relative to costs. In Specific Aim 4. a prototype of the IGART process selected for clinical implementation will be developed. Clinical studies will be performed to confirm IGART feasibility and dose targeting accuracy.